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In the first few decades of after Columbus's voyages, the primary effect was that large numbers of Native Americans were enslaved and forced to work on European projects. Columbus himself was infamous for the brutal way that he treated the Taíno people, the natives of Hispaniola island, forcing them into slave labor in the recently excavated mines. The work was so callous and so brutal that significant percentages of the Hispaniola Taíno population died from overwork and fellow Spaniards reported him to Queen Isabella, who was in turn so enraged at the conduct that she demanded he return to Spain. (Remember that this is the same "humanitarian" Queen Isabella who is responsible for the Spanish Inquisition.) The Native Americans died in record numbers (especially in the Caribbean) within decades of the Spanish arrival, primarily from foreign diseases, but also from this overwork.

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